Metabolism (including hepatic) Flashcards
Metabolism
Effects, phases
Usually reduces the activity of a drug, but some prodrugs are metabolised to active form e.g. enlapril -> enalaprilat, diamorphine -> 6-monoacylmorphine, parecoxib -> valdecoxib
In general, produces a more polar (water soluble) molecule that can be excreted in bile or urine
Two phases:
* Phase I (functionalisation or non-synthetic): oxidation, reduction, hydrolysis
* Phase II (conjugation or synthetic): glucuronidation, sulfation, acetylation, methylation
**Many drugs are metabolised by phase I reaction followed by phase II reaction, however some drugs are modified by phase II reactions only. **
Liver failure: phase I reactions usually affected before phase II, therefore drugs with predominantly phase II metabolism e.g. lorazepam are less affected.
Phase I metabolism
Reactions (4), Mechanisms/ location (7)
Functionalisation or non-synthetic:
* Oxidation
* Reduction
* Hydrolysis
Mechanisms/ locations: (i.e. not entirely in liver)
* Cytochrome P450 system: Many phase I reactions, particularly oxidative pathways, occur in the liver via the cytochrome P450 system
* Mitochondrial enzyme monoamine oxidase metabolises monoamines (adrenaline, noradrenaline, dopamine)
* Cytoplasmic enzyme alcohol dehydrogenase metabolises ethanol -> acetaldehyde -> further oxidised to acetic acid
* Esterases in the cytoplasm of** liver, muscle** etc metabolise esters: etomidate, aspirin, atracurium, remifentanil
* Angiotension-converting enzyme in the lung metabolises AT1-> AT2 and bradykinin
* Hoffman degredation: cisatracurium breaks down spontaneously in in a pH- and temperature-dependent manner in the plasma
* Plasma cholinesterase hydrolyses suxamethonium
Cytochrome p450 system
Description, classification
Non-specific mixed-function oxidase system in the endoplasmic reticulum of the liver (also found in gut mucosa, lung, brain and kidney)
Classed into families and subfamilies by degree of shared amino acid sequence:
* Families are labelled CYP1, CYP2 etc…, share 40% of their amino acid sequence
* Subfamilies are labelled CYP1A, CYP1B etc, share 55% of their amino acid sequence
* Isoforms within a subfamily are labelled CYP1A1, CYP1A2 etc
Note many drugs are metabolised by more than one isoenzyme
Metabolism of methoxyfluorane
Metabolised by CYP2E1 in the kidneys –> high local concentration of fluoride ions -> risk of renal failure
Metabolism of codeine
Genetic variants
Metabolised by cytochrome P450 enzyme CYP2D6
- Variants of CYP2D6 are associated with defective metabolism of codeine
- Some people have multiple copies of CYP2D6, all of which are expressed: ultrafast metabolisers, convert codeine -> morphine very rapidly: experience unpleasant side effects of morphine
Which cytochrome P450 isoforms demonstrate significant genetic polymorphism
CYP2C9: propofol, parexocib, losartan, S-warfarin
CYP2C19: losartan, diazepam, phenytoin, omeprazole, clopidogrel
CYP2D6: codeine, flecanide, metoprolol
Drugs metabolised by CYP2B6
Propofol
Drugs metabolised by CYP2C9
Propofol
Parecoxib
Losartan
S-warfarin
Note: clinically important genetic polymorphisms occur
Drugs metabolised by CYP2C19
Losartan
Diazepam
Phenytoin
Omeprazole
Clopidogrel
Note: genetic polymorphisms occur
Drugs metabolised by CYP2D6
Codeine
Flecanide
Metoprolol
Note: significant genetic polymorphisms
Drugs metabolised by CYP2E1
Sevoflurane
Halothane
Isoflurane
Paracetamol
Drugs metabolised by CYP3A4
Diazepam
Temazepam
Midazolam
Fentanyl
Alfentanil
Lidocaine
Vecuronium
Drugs metabolised by CYP3A5
Diazepam
Phase 2 metabolism
Reactions (4) with examples, effects, locations
Conjugation or synthetic
* Glucuronidation (e.g. morphine, propofol)
* Sulfation (e.g. quinol metabolite of propofol)
* Acetylation (e.g. isoniazid, sulfonamides)
* Methylation (e.g. catechols such as noradrenaline)
Increase the water solubility of the drug or metabolite to allow excretion into bile or urine
Location
* Mainly in hepatic endoplasmic reticulum
* Other sites involved, e.g, acetylation occurs in lung and spleen also
Acetylation
Type of metabolic pathway, location, example of genetic polymorphism
Phase II metabolic pathway in the liver
N-acetyltransferase type 2 (NAT2) metabolises drugs including hydralazine, isonazid
Genetically different isoenzymes acetylate at slow or fast rate: pharmacokinetic and pharmacodynamic profile of hydralazine, isoniazid etc depends on acetylator status of the individual
